Neurotransmitter release cycle (Homo sapiens)

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4, 5, 17, 2311, 31161, 25, 263062, 27, 32217, 1814, 20, 24, 292, 27, 3214, 20, 24, 2914, 20, 2920, 28, 2912352, 27, 323, 14, 20, 299, 10152, 27, 322, 27, 3213MAOA-FAD complex Rab3-RIM complex Noradrenalin loaded synaptic vesicle Dopamine loaded synaptic vesicle SNARE complex clathrin-sculpted acetylcholine transport vesicle lumenEmpty Glutamate Synaptic Vesicle Acetylcholine Loaded Synaptic Vesicle mitochondrial matrixSNARE complex Glutamate loaded synaptic vesicle clathrin-coated endocytic vesicleRab3-RIM complex Docked acetylcholine loaded Synaptic Vesicle Serotonin loaded synaptic vesicle Docked Noradrenalin loaded synaptic vesicle cytosolDocked serotonin loaded synaptic vesicle SNARE complex Noradrenalin loaded synaptic vesicle Docked dopamine loaded synaptic vesicle Empty Acetylcholine Synaptic Vesicle Glutamate loaded synaptic vesicle SNARE complex Docked Glutamate Loaded Synaptic Vesicle clathrin-sculpted monoamine transport vesicle lumenRab3-RIM complex mitochondrial matrixSNARE complex Rab3-RIM complex Rab3-RIM complex Dopamine loaded synaptic vesicle Serotonin loaded synaptic vesicle Acetylcholine Loaded Synaptic Vesicle clathrin-sculpted glutamate transport vesicle lumencytosolRab3-RIM complex RIMS1 STXBP1-1 SLC18A2 SNARE complexSNAP25 SNARE complexSNARE complexATPSYT1 STX1A RIMS1SLC18A2 Glu VAMP2 SYT1 Na+RIMS1 SLC5A7O-acetylcholine OCT2MAOA SYT1RAB3A STX1ASLC22A2SNAP25 5HTCPLX1STXBP1-1 Rab3-RIM complex5HTRAB3A RAB3A RAB3A GluSLC18A2 SLC38A2NH3ADPSTXBP1-1Glutamate loaded synaptic vesicleSTX1A UNC13BVAMP2 STX1A L-GluRAB3A SYT1 STX1A SLC18A2 Neuronal EAATsRab3-RIM complexSNAP25 H2O2STX1A Serotonin loaded synaptic vesicleSTX1A CPLX1SNARE complexCHATSNAP25 SNAP25 NAdSNAP25SYT1 RAB3A STXBP1-1SYT1 H+VAMP2 AcChoRIMS1DASNAP25 VAMP2 STX1A VAMP2 L-GluSYT1 NAd SYT1 SNAP25RAB3A STXBP1-1SYT1SYT1 Na+STXBP1-1Glu RAB3A VAMP2 Dopamine loaded synaptic vesicleDA SNARE complexSTX1A CPLX1 3-Methoxy-4-hydroxyphenylglycolRIMS1 SNAP25SNAP25 CPLX1H+SLC17A7 SLC18A3RAB3A SYT1 RIMS1 GLS dimersSLC18A3 NAdH2OVAMP2 H+PiEmpty Glutamate Synaptic VesicleVAMP2 RAB3A CPLX1 SLC18A2Docked serotonin loaded synaptic vesicleRAB3A RAB3A GluL-GlnNa+CPLX1SYT1 SNAP25 STX1ARIMS1 RIMS1CPLX1 SYT1SynapsinDADocked acetylcholine loaded Synaptic VesicleRIMS1 SNAP25 RAB3A GABA synthesis, release, reuptake and degradationSNAP25H+5HT Docked dopamine loaded synaptic vesicleRAB3AAcChoRab3-RIM complex5HTVAMP2 VAMP2 STXBP1-1 STX1A STXBP1-1 FAD VAMP2 ChoNAd CPLX1 ATPNH4+SLC18A3O-acetylcholine RAB3A SNAP25DA CPLX1 SYT1Empty Acetylcholine Synaptic VesicleAcetylcholine Loaded Synaptic VesicleNoradrenalin loaded synaptic vesicleRIMS1 Na+RIMS1SLC18A3 CPLX1Ac-CoAO2SYT1 L-GlnSLC18A2VAMP2 STX1AChoRIMS1 SLC17A7 VAMP2 DASTX1ASLC18A3 RAB3ARAB3A SLC18A2 VAMP2 SLC17A7 5HT SLC17A7SNAP25 STX1A Docked Noradrenalin loaded synaptic vesicleRab3-RIM complexSYT1 ADPRAB3A STX1ASTXBP1-1SLC18A2 MAOA-FAD complexRab3-RIM complexSTXBP1-1 L-GlnRIMS1 SYT1H2OVAMP2 RIMS1 RAB3A VAMP2 CoA-SHVAMP2 Docked Glutamate Loaded Synaptic VesicleRAB3A 8, 34228, 348, 3422228, 3419, 33222222222222228, 34


Description

Neurotransmitter is stored in the synaptic vesicle in the pre-synaptic terminal prior to its release in the synaptic cleft upon depolarization of the pre-synaptic membrane. The release of the neurotransmitter is a multi-step process that is controlled by electrical signals passing through the axons in form of action potential. Neurotransmitters include glutamate, acetylcholine, nor-epinephrine, dopamine and seratonin. Each of the neurotransmitter cycle is independently described. Original Pathway at Reactome: http://www.reactome.org/PathwayBrowser/#DB=gk_current&FOCUS_SPECIES_ID=48887&FOCUS_PATHWAY_ID=112310

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Bibliography

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History

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CompareRevisionActionTimeUserComment
114636view16:10, 25 January 2021ReactomeTeamReactome version 75
113084view11:14, 2 November 2020ReactomeTeamReactome version 74
112318view15:24, 9 October 2020ReactomeTeamReactome version 73
101217view11:11, 1 November 2018ReactomeTeamreactome version 66
100755view20:36, 31 October 2018ReactomeTeamreactome version 65
100299view19:13, 31 October 2018ReactomeTeamreactome version 64
99845view15:57, 31 October 2018ReactomeTeamreactome version 63
99402view14:34, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99093view12:39, 31 October 2018ReactomeTeamreactome version 62
94499view09:05, 14 September 2017Mkutmonreactome version 61
88044view13:39, 25 July 2016RyanmillerOntology Term : 'signaling pathway pertinent to the brain and nervous system' added !
88043view13:38, 25 July 2016RyanmillerOntology Term : 'signaling pathway' added !
86606view09:22, 11 July 2016ReactomeTeamreactome version 56
83254view10:32, 18 November 2015ReactomeTeamVersion54
81364view12:53, 21 August 2015ReactomeTeamVersion53
76832view08:05, 17 July 2014ReactomeTeamFixed remaining interactions
76536view11:51, 16 July 2014ReactomeTeamFixed remaining interactions
75869view09:52, 11 June 2014ReactomeTeamRe-fixing comment source
75569view10:37, 10 June 2014ReactomeTeamReactome 48 Update
74924view13:45, 8 May 2014AnweshaFixing comment source for displaying WikiPathways description
74568view08:36, 30 April 2014ReactomeTeamReactome46
42089view21:56, 4 March 2011MaintBotAutomatic update
39897view05:55, 21 January 2011MaintBotNew pathway

External references

DataNodes

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NameTypeDatabase referenceComment
3-Methoxy-4-hydroxyphenylglycolMetaboliteCHEBI:16436 (ChEBI)
5HT MetaboliteCHEBI:28790 (ChEBI)
5HTMetaboliteCHEBI:28790 (ChEBI)
ADPMetaboliteCHEBI:16761 (ChEBI)
ATPMetaboliteCHEBI:15422 (ChEBI)
Ac-CoAMetaboliteCHEBI:15351 (ChEBI)
AcChoMetaboliteCHEBI:15355 (ChEBI)
Acetylcholine Loaded Synaptic VesicleComplexREACT_17766 (Reactome)
CHATProteinP28329 (Uniprot-TrEMBL)
CPLX1 ProteinO14810 (Uniprot-TrEMBL)
CPLX1ProteinO14810 (Uniprot-TrEMBL)
ChoMetaboliteCHEBI:15354 (ChEBI)
CoA-SHMetaboliteCHEBI:15346 (ChEBI)
DA MetaboliteCHEBI:18243 (ChEBI)
DAMetaboliteCHEBI:18243 (ChEBI)
Docked Glutamate Loaded Synaptic VesicleComplexREACT_12825 (Reactome) Glutamate synaptic vesicle contains Rab3 ( GTPase), synaptobrevin/VAMP ( V-SNARE), VGLUT1 (Glutamate transporter) and synpatotagmin which is beleived to be a Ca2+ sensor and plays a role in the synaptic vesicle fusion process.
Docked Noradrenalin loaded synaptic vesicleComplexREACT_15843 (Reactome)
Docked acetylcholine loaded Synaptic VesicleComplexREACT_17285 (Reactome) Acetylcholine synaptic vesicle contains Rab3 ( GTPase), synaptobrevin/VAMP ( V-SNARE), VGLUT1 (Glutamate transporter) and synpatotagmin which is beleived to be a Ca2+ sensor and plays a role in the synaptic vesicle fusion process.
Docked dopamine loaded synaptic vesicleComplexREACT_15684 (Reactome)
Docked serotonin loaded synaptic vesicleComplexREACT_17565 (Reactome)
Dopamine loaded synaptic vesicleComplexREACT_15992 (Reactome)
Empty Acetylcholine Synaptic VesicleComplexREACT_12740 (Reactome)
Empty Glutamate Synaptic VesicleComplexREACT_14482 (Reactome)
FAD MetaboliteCHEBI:16238 (ChEBI)
GABA synthesis, release, reuptake and degradationPathwayREACT_23947 (Reactome) GABA is a major inhibitory neurotransmitter in the mammalian central nervous system. GABA modulates neuronal excitability throughout the nervous system. Disruption of GABA neurotransmission leads to many neurological diseases including epilepsy and a general anxiety disorder. GABA is synthesized by two distinct enzymes GAD67 and GAD65 that differ in their cellular localization, functional properties and co-factor requirements. GABA synthesized by GAD65 is used for neurotransmission whereas GABA synthesized by GAD67 is used for processes other than neurotransmission such as synaptogenesis and protection against neuronal injury. GABA is loaded into synaptic vesicle with the help of vesicular inhibitory amino acid transporter or VGAT. GAD65 and VGAT are functionally linked at the synaptic vesicle membrane and GABA synthesized by GAD65 is preferentially loaded into the synaptic vesicle over GABA synthesized in cytoplasm by GAD67.The GABA loaded synaptic vesicles are docked at the plasma membrane with the help of the SNARE complexes and primed by interplay between various proteins including Munc18, complexin etc. Release of GABA loaded synaptic vesicle is initiated by the arrival of action potential at the presynaptic bouton and opening of N or P/Q voltage gated Ca2+ channels. Ca2+ influx results in Ca2+ binding by synaptobrevin, which is a part of the SNARE complex that also includes SNAP25 and syntaxin, leading to synaptic vesicle fusion. Release of GABA in the synaptic cleft leads to binding of GABA by the GABA receptors and post ligand binding events.
GLS dimersREACT_21656 (Reactome)
Glu MetaboliteCHEBI:16015 (ChEBI)
GluMetaboliteCHEBI:16015 (ChEBI)
Glutamate loaded synaptic vesicleComplexREACT_12769 (Reactome)
H+MetaboliteCHEBI:15378 (ChEBI)
H2O2MetaboliteCHEBI:16240 (ChEBI)
H2OMetaboliteCHEBI:15377 (ChEBI)
L-GlnMetaboliteCHEBI:18050 (ChEBI)
L-GluMetaboliteCHEBI:16015 (ChEBI)
MAOA ProteinP21397 (Uniprot-TrEMBL)
MAOA-FAD complexComplexREACT_5113 (Reactome)
NAd MetaboliteCHEBI:18357 (ChEBI)
NAdMetaboliteCHEBI:18357 (ChEBI)
NH3MetaboliteCHEBI:16134 (ChEBI)
NH4+MetaboliteCHEBI:28938 (ChEBI)
Na+MetaboliteCHEBI:29101 (ChEBI)
Neuronal EAATsREACT_14035 (Reactome)
Noradrenalin loaded synaptic vesicleComplexREACT_17964 (Reactome)
O-acetylcholine MetaboliteCHEBI:15355 (ChEBI)
O2MetaboliteCHEBI:15379 (ChEBI)
OCT2ProteinREACT_160574 (Reactome) This CandidateSet contains sequences identified by William Pearson's analysis of Reactome catalyst entities. Catalyst entity sequences were used to identify analagous sequences that shared overall homology and active site homology. Sequences in this Candidate set were identified in an April 24, 2012 analysis.
PiMetaboliteCHEBI:18367 (ChEBI)
RAB3A ProteinP20336 (Uniprot-TrEMBL) Rab3A, located in the synaptic vesicle membrane, interacts with RIM ( Rab3A interacting Molecule) and with Doc2. These interactions are beleived to initiate the process of priming which precedes the fuison of the synaptic vesicle with the plasma membrane.
RAB3AProteinP20336 (Uniprot-TrEMBL) Rab3A, located in the synaptic vesicle membrane, interacts with RIM ( Rab3A interacting Molecule) and with Doc2. These interactions are beleived to initiate the process of priming which precedes the fuison of the synaptic vesicle with the plasma membrane.
RIMS1 ProteinQ86UR5 (Uniprot-TrEMBL)
RIMS1ProteinQ86UR5 (Uniprot-TrEMBL)
Rab3-RIM complexComplexREACT_13268 (Reactome) Rab3A, located in the synaptic vesicle membrane, interacts with RIM ( Rab3A interacting Molecule) and with Doc2. These interactions are beleived to initiate the process of priming which precedes the fuison of the synaptic vesicle with the plasma membrane.
SLC17A7 ProteinQ9P2U7 (Uniprot-TrEMBL)
SLC17A7ProteinQ9P2U7 (Uniprot-TrEMBL)
SLC18A2 ProteinQ05940 (Uniprot-TrEMBL)
SLC18A2ProteinQ05940 (Uniprot-TrEMBL)
SLC18A3 ProteinQ16572 (Uniprot-TrEMBL)
SLC18A3ProteinQ16572 (Uniprot-TrEMBL)
SLC22A2ProteinO15244 (Uniprot-TrEMBL)
SLC38A2ProteinQ96QD8 (Uniprot-TrEMBL)
SLC5A7ProteinQ9GZV3 (Uniprot-TrEMBL)
SNAP25 ProteinP60880 (Uniprot-TrEMBL)
SNAP25ProteinP60880 (Uniprot-TrEMBL)
SNARE complexComplexREACT_12700 (Reactome)
STX1A ProteinQ16623 (Uniprot-TrEMBL)
STX1AProteinQ16623 (Uniprot-TrEMBL)
STXBP1-1 ProteinP61764-1 (Uniprot-TrEMBL) Munc 18 interacts with syntaxin in the plasma membrane, with Mint (Munc 18 interacting) which in turn interacts with CASK and neurexins. Munc18 also interacts with granulophilin. Granulophilin is interacts simultaneously with syntaxin and Munc18. These interactions are believed to be involved in the docking of the synaptic vesicle to the plasma membrane. However, the sequence of events is unclear.
STXBP1-1ProteinP61764-1 (Uniprot-TrEMBL) Munc 18 interacts with syntaxin in the plasma membrane, with Mint (Munc 18 interacting) which in turn interacts with CASK and neurexins. Munc18 also interacts with granulophilin. Granulophilin is interacts simultaneously with syntaxin and Munc18. These interactions are believed to be involved in the docking of the synaptic vesicle to the plasma membrane. However, the sequence of events is unclear.
SYT1 ProteinP21579 (Uniprot-TrEMBL)
SYT1ProteinP21579 (Uniprot-TrEMBL)
Serotonin loaded synaptic vesicleComplexREACT_16110 (Reactome)
SynapsinProteinREACT_18217 (Reactome)
UNC13BProteinO14795 (Uniprot-TrEMBL)
VAMP2 ProteinP63027 (Uniprot-TrEMBL)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
3-Methoxy-4-hydroxyphenylglycolArrowREACT_15390 (Reactome)
5HTArrowREACT_15503 (Reactome)
ADPArrowREACT_13770 (Reactome)
ADPArrowREACT_15379 (Reactome)
ATPREACT_13770 (Reactome)
ATPREACT_15379 (Reactome)
Ac-CoAREACT_15484 (Reactome)
AcChoArrowREACT_15404 (Reactome)
AcChoArrowREACT_15484 (Reactome)
AcChoREACT_15317 (Reactome)
Acetylcholine Loaded Synaptic VesicleArrowREACT_15317 (Reactome)
Acetylcholine Loaded Synaptic VesicleREACT_15483 (Reactome)
Acetylcholine Loaded Synaptic Vesiclemim-catalysisREACT_15483 (Reactome)
CHATmim-catalysisREACT_15484 (Reactome)
CPLX1ArrowREACT_12411 (Reactome)
CPLX1ArrowREACT_15404 (Reactome)
CPLX1ArrowREACT_15448 (Reactome)
CPLX1ArrowREACT_15503 (Reactome)
CPLX1ArrowREACT_15533 (Reactome)
CPLX1REACT_12617 (Reactome)
CPLX1REACT_15338 (Reactome)
CPLX1REACT_15411 (Reactome)
CPLX1REACT_15483 (Reactome)
CPLX1REACT_15517 (Reactome)
ChoArrowREACT_15552 (Reactome)
ChoREACT_15484 (Reactome)
ChoREACT_15552 (Reactome)
CoA-SHArrowREACT_15484 (Reactome)
DAArrowREACT_15533 (Reactome)
Docked Glutamate Loaded Synaptic Vesiclemim-catalysisREACT_12411 (Reactome)
Docked Noradrenalin loaded synaptic vesiclemim-catalysisREACT_15448 (Reactome)
Docked acetylcholine loaded Synaptic Vesiclemim-catalysisREACT_15404 (Reactome)
Docked dopamine loaded synaptic vesiclemim-catalysisREACT_15533 (Reactome)
Docked serotonin loaded synaptic vesicleArrowREACT_15338 (Reactome)
Docked serotonin loaded synaptic vesiclemim-catalysisREACT_15503 (Reactome)
Dopamine loaded synaptic vesicleREACT_15517 (Reactome)
Dopamine loaded synaptic vesiclemim-catalysisREACT_15517 (Reactome)
Empty Acetylcholine Synaptic VesicleREACT_15317 (Reactome)
Empty Glutamate Synaptic VesicleREACT_12503 (Reactome)
Empty Glutamate Synaptic Vesiclemim-catalysisREACT_12503 (Reactome)
GLS dimersmim-catalysisREACT_1700 (Reactome)
GluArrowREACT_12411 (Reactome)
GluArrowREACT_1700 (Reactome)
Glutamate loaded synaptic vesicleREACT_12617 (Reactome)
Glutamate loaded synaptic vesiclemim-catalysisREACT_12617 (Reactome)
H+ArrowREACT_13770 (Reactome)
H+ArrowREACT_15317 (Reactome)
H+ArrowREACT_15379 (Reactome)
H+REACT_13770 (Reactome)
H+REACT_15317 (Reactome)
H+REACT_15379 (Reactome)
H2O2ArrowREACT_15390 (Reactome)
H2OREACT_15390 (Reactome)
H2OREACT_1700 (Reactome)
L-GlnArrowREACT_13763 (Reactome)
L-GlnREACT_13763 (Reactome)
L-GlnREACT_1700 (Reactome)
L-GluREACT_12503 (Reactome)
MAOA-FAD complexmim-catalysisREACT_15390 (Reactome)
NAdArrowREACT_15448 (Reactome)
NAdREACT_15390 (Reactome)
NH3ArrowREACT_15390 (Reactome)
NH4+ArrowREACT_1700 (Reactome)
Na+ArrowREACT_13763 (Reactome)
Na+ArrowREACT_15552 (Reactome)
Na+REACT_13763 (Reactome)
Na+REACT_15552 (Reactome)
Neuronal EAATsmim-catalysisREACT_13574 (Reactome)
Noradrenalin loaded synaptic vesicleREACT_15411 (Reactome)
Noradrenalin loaded synaptic vesiclemim-catalysisREACT_15411 (Reactome)
O2REACT_15390 (Reactome)
OCT2mim-catalysisREACT_15472 (Reactome)
PiArrowREACT_15379 (Reactome)
RAB3AArrowREACT_15338 (Reactome)
RAB3AArrowREACT_15503 (Reactome)
RAB3AArrowREACT_15533 (Reactome)
REACT_12411 (Reactome) Once vesicles are docked, primed and ready to be released fusion of the synaptic vesicle with the plasma membrane can be triggered by an influx of Ca2+ through the voltage gated Ca2+ channels (N, P/Q and R type). Ca2+ influx initiates a cascade of events in which the Ca2+ sensing protein, synaptotagmin-1 (sty-1) is central. Sty-1 promotes the membrane fusion between the synaptic vesicle and the plasma membrane by Ca2+ dependant induction of membrane curvature. Synaptotagmin competes with SNARE complex binding in a Ca2+ dependent manner thereby displacing complexin-1 and causing membrane curvature and fusion of the synaptic vesicle with the plasma membrane. The fusion is characterized by the formation of a trans SNARE complex in which SNAP 25, syntaxin and synaptobrevin along with VGLUT1, the glutamate transporter, synaptotagmin, and Rab3a either become a part of the plasma membrane or membrane delimited in the vesicular membrane. Vesicle fusion ultimately results in the release of the glutamate into the synaptic cleft.
REACT_12503 (Reactome) Nascent synaptic vesicles are loaded with glutamate by VGLUT1 to form glutamate containing synaptic vesicles. This process occurs while the synaptic vesicle is in the cytosol.
REACT_12617 (Reactome) Docking occurs once the synaptic vesicle has moved from the cytoplasm to a region apposed to the plasma membrane. The vesicle is held in close apposition to the plasma membrane by several proteins that bridge the synaptic vesicle to the plasma membrane. Some of these proteins are in the plasma membrane while others are in the synaptic vesicle. Vesicle fusion is preceded by a priming event where molecular interactions between the docked vesicle and the plasma membrane undergo changes. The molecules in the docking and the priming process are known, however, the exact sequence and the precise molecular changes involved in docking and priming are not well dissected. In this reaction the process of docking and priming has been condensed. It is known that Munc18 along with its interactors is critical for membrane docking and fusion events while Munc 13 along with its interacting proteins is central to priming. Munc 13 could act as a positive regulator for the priming recation. Finally the primed fusion complex is clamped in the pre-fusion form by a Complexin. Complexins are Ca2+ independent cytosolic proteins that bind to partly or fully assembled SNARE complexes. Complexins play both a positive and a negative role in the release process.

REACT_13574 (Reactome) Excess L-Glutamate released by the pre-synaptic neuron in the synaptic cleft is cleared by high affinity transporters called the excitatory amino acid transporters (EAATs) to terminate synaptic actions of the neurotransmitter and to recycle these molecules. Five types of EAATs have been identified EAAT1-EAAT5 in the mammalian CNS. EAAT1 and EAAT2 are mainly expressed by astrocytes whereas EAAT3 and EAAT4 are predominantly neuronal. EAAT3 are expressed throughout the CNS however, EAAT4 is predominantly localized to purkinje cells. EAAT5 are expressed rod photoreceptor and bipolar cells of retina. Astrocytic EAATs are expressed in astrocytes in close apposition to the synapses and neuronal EAATs are expressed in the extra-synaptic or peri-synaptic locations on the neurons. Astrocytic EAATs are responsible for majority of the glutamate uptake, neuronal transporters are responsible for glutamate clearance in specialized synapses in cerebellum where the spatial relationship between the glutamate receptors and EAATs is altered and glutamate receptors are expressed in the peri-synaptic region.
REACT_13703 (Reactome) Glutamine in neurons is transported into mitochondrial matrix by an unknown transporter. Because this enzyme is not yet identified, it is represented as a black box event.
REACT_13763 (Reactome) Glutamine uptake in neurons is carried out by Na+-dependant system A neutral amino acid transporter (Melone et al. 2006).
REACT_13770 (Reactome) The proton gradient for the acetylcholine uptake is provided by vH+ type ATPase pump located in the acetylcholine vesicular membrane.
REACT_13790 (Reactome) Glutamate from the mitochondrial matrix is transported back into the cytosol, to be loaded into synaptic vesicles. Solute carrier 25 is a mitochondrial glutamate transporter known to transport glutamate, but it is unclear if this protein is involved in the transport of glutamate in neurons.
REACT_15317 (Reactome) Acetylcholine is actively transported from the cytosol to the lumen of the clathrin sculpted synaptic vesicle by vesicular acetylcholine transporter. Two protons are exchanged for 1 molecule of acetylcholine. The vesicular acetylcholine transporter is located in the membrane of the clathrin sculpted synaptic vesicle.
REACT_15338 (Reactome) Serotonin loaded synaptic vesicles are docked, inside the synapse in the presynaptic cell, close to the plasmamembrane. The docking brings the vesicles in close proximity to the release site to fascilitate the release of serotonin. Some of the molecules involved in the docking process are Munc 18, Rab3a, Rab 3 interacting molecule (RIM). The priming reaction brings docked but unprimed synaptic vesicles into a releaseable pool. Priming involes formation of the trimeric SNARE complex between two plasmamembrane proteins SNAP25 and Syntaxin and vesicular membrane protein, VAMP2.
REACT_15379 (Reactome) Loading of the monoamine vesicle is preceded by acidifcation of the vesicle by ATPAse.
REACT_15390 (Reactome) Noradrenaline is degraded by Monoamine oxidase A, which contains FAD as a cofactor. Monoamine oxidase is located in the outer mitochondrial membrane facing the cytoplasmic site. Monoamine xoidase functions as a monomer and is functional both is astrocyes and neurons.
REACT_15404 (Reactome) Once vesicles are docked, primed and ready to be released fusion of the synaptic vesicle with the plasma membrane can be triggered by an influx of Ca2+ through the voltage gated Ca2+ channels (N, P/Q and R type). Ca2+ influx initiates a cascade of events in which the Ca2+ sensing protein, synaptotagmin-1 (sty-1) is central. Sty-1 promotes the membrane fusion between the synaptic vesicle and the plasma membrane by Ca2+ dependant induction of membrane curvature. Synaptotagmin competes with SNARE complex binding in a Ca2+ dependent manner thereby displacing complexin-1 and causing membrane curvature and fusion of the synaptic vesicle with the plasma membrane. The fusion is characterized by the formation of a trans SNARE complex in which SNAP 25, syntaxin and synaptobrevin along with VGLUT1, the glutamate transporter, synaptotagmin, and Rab3a either become a part of the plasma membrane or membrane delimited in the vesicular membrane. Vesicle fusion ultimately results in the release of the acetylcholine into the synaptic cleft.
REACT_15411 (Reactome) Docking and priming of clathrin sculpted Noradrenaline loaded transport vesicle occurs once the synaptic vesicle has moved from the cytoplasm to a region apposed to the plasma membrane. The details of the docking and priming recation have been worked out using synaptic vesicle loaded with glutamate and similar reactions may occur during the transport cycle of noradrenaline. The vesicle is held in close apposition to the plasma membrane by several proteins that bridge the synaptic vesicle to the plasma membrane. Some of these proteins are in the plasma membrane while others are in the synaptic vesicle. Vesicle fusion is preceded by a priming event where molecular interactions between the docked vesicle and the plasma membrane undergo changes. The molecules in the docking and the priming process are known, however, the exact sequence and the precise molecular changes involved in docking and priming are not well dissected. In this reaction the process of docking and priming has been condensed. It is known that Munc18 along with its interactors is critical for membrane docking and fusion events while Munc 13 along with its interacting proteins is central to priming. Munc 13 could act as a positive regulator for the priming recation. Finally the primed fusion complex is clamped in the pre-fusion form by a Complexin. Complexins are Ca2+ independent cytosolic proteins that bind to partly or fully assembled SNARE complexes. Complexins play both a positive and a negative role in the release process.

REACT_15448 (Reactome) Once vesicles are docked, primed and ready to be released fusion of the synaptic vesicle with the plasma membrane can be triggered by an influx of Ca2+ through the voltage gated Ca2+ channels (N, P/Q and R type). Ca2+ influx initiates a cascade of events in which the Ca2+ sensing protein, synaptotagmin-1 (sty-1) is central. Sty-1 promotes the membrane fusion between the synaptic vesicle and the plasma membrane by Ca2+ dependant induction of membrane curvature. Synaptotagmin competes with SNARE complex binding in a Ca2+ dependent manner thereby displacing complexin-1 and causing membrane curvature and fusion of the synaptic vesicle with the plasma membrane. The fusion is characterized by the formation of a trans SNARE complex in which SNAP 25, syntaxin and synaptobrevin along with VGLUT1, the glutamate transporter, synaptotagmin, and Rab3a either become a part of the plasma membrane or membrane delimited in the vesicular membrane. Vesicle fusion ultimately results in the release of the noradrenalin into the synaptic cleft.
REACT_15472 (Reactome) Noradrenaline is cleared from the synaptic cleft by Noaradrenaline uptake transporter. This reaction is carried out by neurons as well as astrocytes.
REACT_15483 (Reactome) Docking and priming of clathrin sculpted acetylcholine loaded transport vesicle occurs once the synaptic vesicle has moved from the cytoplasm to a region apposed to the plasma membrane. The details of the docking and priming reaction have been worked out using synaptic vesicles loaded with glutamate and similar reactions may occur during the transport cycle of acetylcholine. The vesicle is held in close apposition to the plasma membrane by several proteins that bridge the synaptic vesicle to the plasma membrane. Some of these proteins are in the plasma membrane while others are in the synaptic vesicle. Vesicle fusion is preceded by a priming event where molecular interactions between the docked vesicle and the plasma membrane undergo changes. The molecules in the docking and the priming process are known, however, the exact sequence and the precise molecular changes involved in docking and priming are not well dissected. In this reaction the process of docking and priming has been condensed. It is known that Munc18 along with its interactors is critical for membrane docking and fusion events while Munc 13 along with its interacting proteins is central to priming. Munc 13 could act as a positive regulator for the priming recation. Finally the primed fusion complex is clamped in the pre-fusion form by a Complexin. Complexins are Ca2+ independent cytosolic proteins that bind to partly or fully assembled SNARE complexes. Complexins play both a positive and a negative role in the release process.

REACT_15484 (Reactome) In the cytosol, choline O-acetyltransferase (CHAT) acetylates choline (Cho) to produce acetylcholine (AcCho) (Toussaint 1992).

AcCho is synthesised in the cytoplasm of cholinergic neurons from acetyl-CoA and Cho by CHAT enzyme.
REACT_15486 (Reactome) Serotonin is loaded into the clathrin sculpted monoamine transport vesicle by vesicular monoamine transporter.
REACT_15503 (Reactome) The trimeric complex formed between V-SNARE (VAMP) and the T-SNAREs (syntaxin and SNAP 25) after priming step is called transSNARE complex because the members of each group lie on the opposide side of the membrane, plasmamembrane side and the vesicular membrane side. Ca2+ influx through the Voltage gated Calcium Channels (VGCC) initaites the process of fusion of the synaptic vesicle in the presynaptic cell. The rise in Ca2+ leads to the activation of Protein Kinase A through rise in cAMP. Synaptotagmin, a Ca2+ sensor proetin also plays a role in the fusion process. Following fusion the members of V and T SNARES lie on the same membrane formin the cis-SNARES. The fusion of release causes the release of the neurotransmitter into the synaptic cleft.
REACT_15517 (Reactome) Dopamine loaded synaptic vesicles are docked, inside the synapse in the presynaptic cell, close to the plasmamembrane. The docking brings the vesicles in close proximity to the release site to fascilitate the release of dopamine. Some of the molecules involved in the docking process are Munc 18, Rab3a, Rab 3 interacting molecule (RIM). The priming reaction brings docked but unprimed synaptic vesicles into a releaseable pool. Priming involes formation of the trimeric SNARE complex between two plasmamembrane proteins SNAP25 and Syntaxin and vesicular membrane protein, VAMP2.
REACT_15524 (Reactome) Dopamine is transported from the cytosol into the reacidified clathrin sculpted monoamine transport vesicle by membranous vesicular monoamine transporter
REACT_15533 (Reactome) The trimeric complex formed between V-SNARE (VAMP) and the T-SNAREs (syntaxin and SNAP 25) after priming step is called transSNARE complex because the members of each group lie on the opposide side of the membrane, plasmamembrane side and the vesicular membrane side. Ca2+ influx through the Voltage gated Calcium Channels (VGCC) initaites the process of fusion of the synaptic vesicle in the presynaptic cell. The rise in Ca2+ leads to the activation of Protein Kinase A through rise in cAMP. Synaptotagmin, a Ca2+ sensor proetin also plays a role in the fusion process. Following fusion the members of V and T SNARES lie on the same membrane formin the cis-SNARES. The fusion of release causes the release of the neurotransmitter into the synaptic cleft.
REACT_15552 (Reactome) Choline transporter symports Na ion and Choline from the extracellular region into the cytosol. The choline transporters are located in the nerve terminals of cholinergic neurons.
REACT_1700 (Reactome) Mitochondrial glutaminase (GLS) catalyzes the hydrolysis of glutamine to yield glutamate and ammonia. Two GLS enzymes have been identified, one abundantly expressed in the liver (GLS - Elgadi et al. 1999) and one abundantly expressed in kidney (GLS2 - Gomez-Fabre et al. 2000). Their biochemical properties are similar. The enzymes are inferred to function as dimers based on unpublished crystallographic data for GLS (PDB 3CZD) and studies of glutaminase enzyme purified from Ehrlich Ascites cells (Quesada et al. 1988).
RIMS1ArrowREACT_15503 (Reactome)
RIMS1ArrowREACT_15533 (Reactome)
RIMS1REACT_12617 (Reactome)
RIMS1REACT_15411 (Reactome)
RIMS1REACT_15483 (Reactome)
Rab3-RIM complexArrowREACT_12411 (Reactome)
Rab3-RIM complexArrowREACT_15404 (Reactome)
Rab3-RIM complexArrowREACT_15448 (Reactome)
Rab3-RIM complexREACT_15338 (Reactome)
Rab3-RIM complexREACT_15517 (Reactome)
SLC17A7ArrowREACT_12411 (Reactome)
SLC18A2ArrowREACT_15448 (Reactome)
SLC18A2ArrowREACT_15503 (Reactome)
SLC18A2ArrowREACT_15533 (Reactome)
SLC18A2mim-catalysisREACT_15486 (Reactome)
SLC18A2mim-catalysisREACT_15524 (Reactome)
SLC18A3ArrowREACT_15404 (Reactome)
SLC18A3mim-catalysisREACT_15317 (Reactome)
SLC38A2mim-catalysisREACT_13763 (Reactome)
SLC5A7mim-catalysisREACT_15552 (Reactome)
SNAP25REACT_12617 (Reactome)
SNAP25REACT_15338 (Reactome)
SNAP25REACT_15411 (Reactome)
SNAP25REACT_15483 (Reactome)
SNAP25REACT_15517 (Reactome)
SNARE complexArrowREACT_12411 (Reactome)
SNARE complexArrowREACT_15404 (Reactome)
SNARE complexArrowREACT_15448 (Reactome)
SNARE complexArrowREACT_15503 (Reactome)
SNARE complexArrowREACT_15533 (Reactome)
STX1AREACT_12617 (Reactome)
STX1AREACT_15338 (Reactome)
STX1AREACT_15411 (Reactome)
STX1AREACT_15483 (Reactome)
STX1AREACT_15517 (Reactome)
STXBP1-1ArrowREACT_12411 (Reactome)
STXBP1-1ArrowREACT_15404 (Reactome)
STXBP1-1ArrowREACT_15448 (Reactome)
STXBP1-1ArrowREACT_15503 (Reactome)
STXBP1-1ArrowREACT_15533 (Reactome)
STXBP1-1REACT_12617 (Reactome)
STXBP1-1REACT_15338 (Reactome)
STXBP1-1REACT_15411 (Reactome)
STXBP1-1REACT_15483 (Reactome)
STXBP1-1REACT_15517 (Reactome)
SYT1ArrowREACT_12411 (Reactome)
SYT1ArrowREACT_15404 (Reactome)
SYT1ArrowREACT_15448 (Reactome)
SYT1ArrowREACT_15503 (Reactome)
SYT1ArrowREACT_15533 (Reactome)
Serotonin loaded synaptic vesicleREACT_15338 (Reactome)
Serotonin loaded synaptic vesiclemim-catalysisREACT_15338 (Reactome)
SynapsinArrowREACT_15503 (Reactome)
SynapsinArrowREACT_15533 (Reactome)
SynapsinREACT_15338 (Reactome)
SynapsinREACT_15517 (Reactome)
UNC13BArrowREACT_12617 (Reactome)
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